Substance abuse causes long-term, if not permanent alterations of brain function, which are thought to at least partly reside in structural reorganization in cortical areas and subcortical brain reward pathways. The Nogo signaling system that upon binding to receptor complexes comprised of the Nogo receptor (NgR1) in conjunction with coreceptors residing in nerve cell membranes will cause inhibition of nerve fiber growth. NgR is also effectively down-regulated by increased neuronal activity and we postulated this to be a key factor in the plasticity needed to form lasting (one month) memories. In support of our hypothesis mice carrying an inducible NgR transgene ("MemoFlex") in forebrain neurons, cannot form lasting memories when the transgene is active (See Karl[unreadable]n 2009 et al.). In these "MemoFlex" mice LTP and 1 day memories are normal. We propose to characterize the role of NgR using NgR null mutant and overexpressing "MemoFlex" mice in behavioral models for drug responses that require long term (>4 weeks) memory. Reinstatement of conditioned place preference (CPP) for environments previously paired with receipt of addictive drugs, and how NgR affects sensitization to drug induced locomotor responses will be analyzed. Both models use a drug free period of 4 weeks before the animal's behaviors are reinstated with a low priming dose of the drug. Structural changes such as dendritic spine alterations in brain reward pathways after addictive drugs or a natural reward, wheel running, will be analyzed in the same mice. Finally, activity in metabolic pathways that are important for structural plasticity and levels of the neurotrophic factor BDNF and (FosB which are both upregulated in accumbens after addictive drugs and wheel running will be analyzed. The project aims at revealing the roles of the Nogo system for the structural plasticity, learning and memory events in brain pathways needed for development and maintenance of addiction. We will test the hypothesis that structural reorganization in cortical and subcortical telenecephalic areas underlie long term correlates of the transition between drug exposure and addiction in unique mouse models. To our knowledge the Nogo system has never been analyzed in models of addiction. This research will also help determine if the NgR signaling pathways may offer new targets for the development of treatments for drug addiction. PUBLIC HEALTH RELEVANCE: Consumption of addictive drugs form very stable drug associated memories, which are likely to be very important for the development and maintenance of compulsive drug consuming behaviors. In this project we aim to characterize the role of the Nogo receptor, which has a key function in long- term memory and structural rearrangement of the brain. If successful this program can open up for the development of new treatments for drug addicts, which targets Nogo receptor signaling